Licorice and Women’s Health

By Adriane Fugh-Berman, MD

Our audience is like people who like licorice. Not everyone likes licorice, but the people who like licorice really like licorice.

—Jerry Garcia

Licorice candies are very popular in many countries, including Holland, Denmark, Finland, Sweden, Germany, Italy, and the United States. Licorice also is popular in beverages ranging from herbal teas to liqueurs (including arak, ouzo, and pastis); "brewer’s licorice" may be added to porter and stout for both flavor and color.

Red or strawberry licorice (shudder) contains no licorice at all, and even black licorice in the United States usually is flavored with anise rather than licorice. Licorice from other countries is real licorice, and often is combined with salt, peppermint, or other flavors.

A perennial plant with sweet-tasting roots, licorice (Glycyrrhiza glabra L.) is native to Asia, Russia, the Middle East, and the Mediterranean, and is widely used as a flavoring, sweetener, and medicinal herb. Licorice root contains triterpenoid saponins, especially glycyrrhizin. Also called glycyrrhizic or glycyrrhizinic acid (GL), glycyrrhizin is 50 times sweeter than sugar, so licorice often is used as a natural sweetener, as well as a flavoring. GL is hydrolyzed to glycyrrhetinic acid (GA) in the intestine, apparently by intestinal bacteria.

Medicinal Use

Licorice and its derivatives were once used in conventional medicine in the United States for treating peptic ulcers, and numerous older studies found licorice and licorice compounds effective in ulcer treatment. However, the treatment fell out of favor because of side effects.1 The effect of licorice on cortisol levels once was exploited medicinally; licorice formerly was used to treat Addison’s disease.2 Licorice is one of the most common ingredients in traditional Chinese herbal mixtures, and also is used by Western herbal practitioners to treat mouth ulcers, peptic ulcers, cough, and respiratory infections, and as an anti-inflammatory and an immune system stimulant.

Licorice Toxicity

Reported cases of licorice toxicity have been associated with licorice-containing liqueurs, candies, chewing gum, laxatives, and chewing tobacco, not from the use of licorice in herbal medicine. Licorice is a very common component of Chinese and Western herbal medicines but almost always is used as part of a mixture (in addition to its therapeutic effects, the sweet taste of licorice may render some herbal mixtures more palatable). The synergistic effects of mixtures, as well as dose differences and short duration of use, may minimize adverse reactions.

Licorice inhibits 11b-hydroxysteroid dehydrogenase, which converts cortisol to cortisone. Cortisol has the same binding affinity as aldosterone, whereas cortisone has a lower binding affinity to mineralocorticoid receptors. In the kidney, inhibition of 11b-hydroxysteroid dehydrogenase produces high renal levels of cortisol, resulting in a state of apparent mineralocorticoid excess that resembles 11b-hydroxysteroid dehydrogenase deficiency.3

In 10 healthy volunteers, GL 500 mg/d produced marked glucocorticoid activity, elevating urinary excretion of free cortisol, decreasing urinary free cortisone, and decreasing plasma cortisone (plasma cortisol was unchanged).4 Eleven volunteers given licorice for 10 days experienced decreased plasma renin activity and decreased urinary aldosterone, indicating significant suppression of the renin-angiotensin-aldosterone system. Urinary free cortisol rose in all subjects.5 Suppression of the renin-angiotensin-aldosterone system may last for several months.3 In men, licorice (7 g, containing 500 mg GL daily for a week) significantly decreased testosterone and 17-hydroxyprogesterone levels.6

Cardiovascular Effects

Many people, including myself, consume licorice incessantly with no problems. While the prevalence of licorice toxicity is unknown, it is not common. In Denmark, the average licorice consumption per person is 2 kg/yr, and no epidemics of licorice toxicity have been reported. One study of Danish school children between 6 and 18 years of age found no linear relationship between licorice consumption and blood pressure.7

Some individuals, however, are susceptible to licorice toxicity, and women seem more susceptible than men. The classic picture of licorice toxicity is pseudoprimary aldosteronism; symptoms may include edema, hypertension, and hypokalemia.8,9 Cardiac arrest, including two deaths, have been associated with excessive licorice use. Cardiomyopathy also has been reported.10

Excessive acute use of licorice also can cause adverse effects. A case of hypertension encephalopathy was reported in a 15-year-old three hours after eating 0.5 kg licorice;11 ingestion of 1 kg licorice by a 25-year-old woman with myeloid leukemia caused decerebrate rigidity, tetraparesis, and coma.12 Pulmonary edema was reported in a previously healthy, 64-year-old man who had eaten four packages (1,020 g) of Twizzlers (one of the few American "licorice" brands that contains real licorice) over three days; total GL consumed was approximately 3.6 g.13

Ingestion of 100 g licorice daily for four weeks in 30 normotensive subjects resulted in a significant (6.5 mm Hg) increase in systolic blood pressure, which had not returned to baseline 2-4 weeks after licorice consumption ended.14 Diastolic blood pressure did not change significantly. Serum potassium decreased 0.24 mmol/L.

This experiment found that women were more sensitive to licorice than were men; blood pressures were slightly higher for women and 14 of 19 women gained weight (mean 0.59 kg; one women gained 6.8 kg); there was no significant weight gain in men. The experiment was repeated in 13 women who had been in the original study. With a lower dose of 50 g licorice, systolic blood pressure rose 5.6 mm Hg and diastolic blood pressure rose 3.4 mm Hg.

Hypokalemia

An analysis of 59 cases of licorice-associated hypokalemic myopathy noted that many patients had additional risk factors for hypokalemia, including alcoholism, diarrhea, or diuretic use.15 Severe hypokalemia may result in rhabdomyolysis. Several cases of licorice-associated rhabdomyolysis have been reported, including the case of a 62-year-old Muslim man on diuretic therapy who developed weakness and pain during the holy month of Ramadan, during which observers fast during the day and often consume a licorice-containing soft drink during the evening meal. Apparently the fasting, diuretic use, and licorice consumption proved synergistic for hypokalemia.16

Licorice and Preterm Birth

A survey of 1,049 Finnish women who gave birth to singleton infants in 1998 examined the effect of licorice on birth outcome.17 Almost half of the mothers surveyed (46%) reported weekly licorice consumption, and only 2.3% of respondents never consumed licorice during pregnancy. The women were grouped by glycyrrhizin exposure (low: < 250 mg/wk; moderate: 250-499 mg/wk; and heavy: > 500 mg/wk).

Compared to babies exposed to the lowest levels of maternal licorice, babies exposed to the highest levels were significantly more likely to be born before 38 weeks gestation (odds ratio 2.5, 95% confidence interval 1.1, 5.5, P = 0.03). Adjustments were made for sex, maternal age, parity, smoking, coffee consumption, and systolic blood pressure. Heavy licorice consumption was associated with a mean shortening of gestation of 2.52 days. The researchers suggest that possible mechanisms include inhibition of cortisol metabolism (cortisol stimulates corticotropin-releasing hormone from the placenta, and is thought to be a parturition trigger) or possibly increased uterine prostaglandin levels through inhibition of 15-b-hydroxyprostaglandin dehydrogenase (a homologue of 11-b-hydroxysteroid dehydrogenase).

Drug Interactions

Licorice potentiates corticosteroids; oral admini- stration increases the plasma concentration of pred- nisolone and topical GL potentiates the action of hydrocortisone.18

Oral Contraceptives

Combined oral contraceptives may increase sensitivity to GA. Two cases of hypokalemia and hypertension were reported in oral contraceptive users who used licorice chewing gum; one consumed about 120 mg GL daily, and another consumed 50 mg GL daily (this is notable because these are low levels of consumption; most reports of adverse effects occur with consumption of ³ 400 mg GL per day).19

Advising Patients

So what is a safe range for licorice ingestion? There is clearly significant individual variation; 100 mg GL daily (about 50 g or 1.75 oz of candy) can produce adverse effects in some people, and most people who consume more than 400 mg GL daily will experience symptoms.3 Some individuals, however, are hypersensitive to glycyrrhizin; doses as low as 20 mg/d GL have produced severe hypokalemia.20

A no-effect level study in 39 healthy women tested the effects of orally administered GL (1, 2, and 4 mg/kg body weight) for eight weeks.21 The authors proposed a no-effect level of 2 mg/kg, and extrapolated an acceptable daily intake of 0.2 mg/kg body weight. Assuming that licorice contains 0.2% GL, a 60 kg person should ingest no more than 6 g (one fifth of an ounce) of licorice (containing 12 mg GL) daily.

References

1. Schambelan M. Licorice ingestion and blood pressure regulating hormones. Steroids 1994;59:127-130.

2. Groen J, et al. Extract of licorice for the treatment of Addison’s disease. N Engl J Med 1951;244:471-475.

3. Størmer FC, et al. Glycyrrhizic acid in liquorice—evaluation of health hazard. Food Chem Toxicol 1993;31: 303-312.

4. MacKenzie MA, et al. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers. J Clin Endocrinol Metab 1990;70: 1637-1643.

5. Stewart PM, et al. Mineralocorticoid activity of liquorice: 11-beta hydroxysteroid dehydrogenase deficiency comes of age. Lancet 1987;2:821-824.

6. Armanini D, et al. Reduction of serum testosterone in men by licorice. N Engl J Med 1999;341:1158.

7. Ibsen KK. Liquorice consumption and its influence on blood pressure in Danish school-children. Dan Med Bull 1981;28:124-126.

8. Farese RV Jr, et al. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991;325:1223-1227.

9. Epstein MT, et al. Effect of eating liquorice on the renin-angiotensin aldosterone axis in normal subjects. BMJ 1977;1:488-490.

10. Chandler RF. Glycyrrhiza glabra. In: De Smet PAGM, et al, eds. Adverse Effects of Herbal Drugs. Berlin: Springer-Verlag; 1997.

11. Van der Zwan A. Hypertension encephalopathy after liquorice ingestion. Clin Neurol Neurosurg 1993;95: 35-37.

12. Hupperets P, et al. Reversible coma due to hypo-kalaemia in a patient treated for acute leukaemia. Neth J Med 1983;26:21-22.

13. Chamberlain JJ, Abolnik IZ. Pulmonary edema following a licorice binge. West J Med 1997;167:184-185.

14. Sigurjonsdottir HA, et al. Is blood pressure commonly raised by moderate consumption of liquorice? J Hum Hypertens 1995;9:345-348.

15. Shintani S, et al. Glycyrrhizin (licorice)-induced hypokalemic myopathy. Report of two cases and review of the literature. Eur Neurol 1992;32:44-51.

16. Achar KN, et al. Severe hypokalemic rhabdomyolysis due to ingestion of liquorice during Ramadan. Aust N Z J Med 1989;19:365-367.

17. Strandberg TE, et al. Birth outcome in relation to licorice consumption during pregnancy. Am J Epidemiol 2001;153:1085-1088.

18. Teelucksingh S, et al. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990; 335:1060-1063.

19. de Klerk GJ, et al. Hypokalaemia and hypertension associated with use of liquorice flavoured chewing gum. BMJ 1997;314:731-732.

20. Chubachi A, et al. Acute renal failure following hypokalemic rhabdomyolysis due to chronic glycyrrhizic acid administration. Intern Med 1992;31:708-711.

21. van Gelderen CE, et al. Glycyrrhizic acid: The assessment of a no effect level. Hum Exp Toxicol 2000;19: 434-439.